Abstract
Aim
This study evaluated the long‐term safety and efficacy of venlafaxine extended release (ER), which has been administered for 52 weeks in Japanese adult outpatients with generalized anxiety disorder (GAD).
Methods
In this open‐label, long‐term extension, multicenter study, 135 Japanese patients with GAD were enrolled after completing 10 weeks of treatment with venlafaxine ER or placebo (including tapering) during the preceding placebo‐controlled, double‐blind study. Venlafaxine ER 75–225 mg/day was to be administered to all participants for 52 weeks in this study. Primary endpoints were the incidence of adverse events and suicidal ideation/behavior. Secondary endpoints included scores of the Hamilton Anxiety Rating Scale (HAM‐A), Clinical Global Impressions‐Severity of Illness (CGI‐S), and Clinical Global Impressions‐Global Improvement (CGI‐I).
Results
Venlafaxine ER was overall well‐tolerated. Reported adverse events were in line with those reported in the preceding placebo‐controlled, double‐blind study. No serious adverse events or deaths were reported, and no tendency of venlafaxine ER to induce suicidal ideation was observed. No new safety findings were identified. A constant and consistent decrease in mean HAM‐A total scores was observed (baseline: 15.9; Week 52: 8.0), as evidenced by a more pronounced change from baseline. Similar improvements were also observed in CGI‐S and CGI‐I scores, suggesting the effectiveness of venlafaxine ER with long‐term use.
Conclusion
The overall safety profile with long‐term use of venlafaxine ER was consistent with the one previously observed, confirming the safety of long‐term use of venlafaxine ER in Japanese adult patients with GAD.
Keywords: generalized anxiety disorder, Japan, long‐term extension study, long‐term safety, venlafaxine
INTRODUCTION
Generalized anxiety disorder (GAD) is a chronic and recurring psychiatric disorder, whose core symptom is not anxiety triggered by specific situations but rather persistent (at least 6 months), excessive, and uncontrollable anxiety or worry from various events or activities. As it is often associated with somatic symptoms and pathological behavioral changes, 1 , 2 it is diagnosed by considering the presence or absence of any concurrent somatic illnesses and the extent of the impact on patients' day‐to‐day activities from their somatic symptoms. For the diagnosis of GAD, the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM‐5) 3 is currently used as a major diagnostic criterion and one of the modern classification systems. 1 , 3 , 4 , 5
Based on the data from 26 World Mental Health (WMH) surveys carried out in 23 countries, 6 lifetime prevalence of GAD was 4.5% across all WMH surveys and 2.6% in Japan. A web‐based cross‐sectional survey of approximately 20,000 Japanese participants using a questionnaire reported that the overall prevalence of probable GAD, based on the Generalized Anxiety Disorder 7‐item (GAD‐7) cutoff score of 10 or higher, was 7.6%. 7 While the surveys indicate the prevalence of GAD in Japan, it is believed that the rates of medical consultation and awareness of the disease are low among patients with GAD. Further, even if patients visit a medical institution, few receive an appropriate diagnosis and treatment. 7
Furthermore, GAD is a serious and chronic condition that requires appropriate long‐term treatment. 8 Given its recurrent and persistent nature, long‐term treatment strategies are essential not only for acute symptom relief but also for maintaining remission and preventing relapse.
The primary treatments for GAD include pharmacotherapy and cognitive behavioral therapy, with selective serotonin reuptake inhibitors and serotonin‐norepinephrine reuptake inhibitors (SNRIs), are recommended as first‐line drug therapies according to relevant international guidelines. 9 , 10 , 11 In addition, there are some cases for which a long‐term treatment is needed to maintain remission of the disease and/or prevent recurrence. In Japan, evidence supporting long‐term treatment remains limited, and physicians use international guidelines as references to consider publicly disclosed efficacy results and their own experience to determine appropriate treatment strategies for patients with GAD. 12
Venlafaxine is an antidepressant classified as an SNRI, and its extended release (ER) formulation was first approved in 1997. It has been approved for the indications of major depressive disorder (MDD), social anxiety disorder, and panic disorder outside Japan, and depression or a depressive state in Japan. 13 Venlafaxine ER has also been approved for the indication of GAD in over 70 countries, and this indication has recently been added in Japan as well. For the treatment with venlafaxine ER in patients with GAD, clinical evidence of its efficacy and safety has been globally established by the results from five Phase 3 clinical studies. The acute efficacy and safety of venlafaxine ER were demonstrated in three short‐term placebo‐controlled studies, where venlafaxine was administered at fixed doses for 8 weeks, 14 , 15 , 16 and the long‐term efficacy and safety were reported in two long‐term placebo‐controlled studies, where it was administered at fixed doses 17 or flexible doses 18 for 6 months. In Japan, since venlafaxine ER was approved for the indication of depression or a depressive state in 2015, its safety profile in Japanese patients has been established. In addition, a Phase 3, double‐blind, randomized study with venlafaxine ER administered at flexible doses over 8 weeks followed by a 2‑week tapering period (total duration, 10 weeks) was conducted in Japan to examine the efficacy and safety in Japanese adult outpatients with GAD. 19 The double‐blind Phase 3 study evaluated and confirmed the previous expectation that the beneficial profile for GAD patients is essentially comparable between Japanese and other ethnicities, as venlafaxine had already shown a favorable benefit‐risk ratio for GAD in multiple historical clinical studies in ethnicities other than Asia. 14 , 15 , 16 , 17 , 18 Although long‐term treatment strategies aimed at maintaining remission and preventing relapse are essential for GAD, evidence supporting long‐term treatment remains limited in Japan. To address this gap and better understand the safety and efficacy of a long‐term treatment with venlafaxine ER in Japanese outpatients with GAD, we report findings on safety and efficacy of venlafaxine ER 75–225 mg/day for 52 weeks in an open‐label, long‐term extension study subsequent to the above‐mentioned short‐term, Phase 3, double‐blind, randomized study, during which a tapering period was included but administration of venlafaxine ER was continuously maintained without any treatment‐free interval.
METHODS
This open‐label, long‐term extension, multicenter study was conducted following a 10‐week, double‐blind, randomized study to evaluate the safety and efficacy of venlafaxine ER in Japanese outpatients with GAD, based on the DSM‐5 diagnostic criteria. 3 The study was conducted across 30 study sites in Japan from November 2022 to October 2024. Signed informed consent was obtained from all participants after a tapering period had been completed in the preceding study, and a full explanation of the study was provided prior to the initiation of any study‐specific procedures/activities. This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and was consistent with Good Clinical Practices and applicable regulatory requirements.
Study design
This study consisted of a 52‐week treatment period and a 1‐ to 3‐week tapering period. GAD patients were enrolled in the study who had completed a preceding 10‐week study and had shown good tolerability to venlafaxine ER or placebo. The number of participants was capped to 135 in this study. Participants in both the venlafaxine and placebo groups of the preceding study received venlafaxine ER for 52 weeks before entering the 1‐ to 3‐week tapering period. Participants who discontinued the study intervention during the 52‐week treatment period were also switched to the tapering period. Follow‐up assessments were conducted 4 weeks after the last dose of venlafaxine ER for all participants (Supporting Information S1: Figure 1).
Venlafaxine ER was administered orally once a day in the evening after food. If participants had difficulty with this dosing schedule, administration once daily in the morning after eating was allowed as an alternative. As in the preceding study, the present study employed the same dosing range approved for the indication of depression or a depressive state in Japan. Participants received venlafaxine ER 37.5 mg/day for the first week and then 75 mg/day for the second week. From the third week onwards during the treatment period, participants received a flexible dose of either venlafaxine ER 75, 150, or 225 mg/day according to their disease symptoms (Clinical Global Impressions‐Global Improvement [CGI‐I] and tolerability) and following a pre‐defined dose‐escalation scheme. After the completion of the treatment period or at discontinuation, participants were required to gradually reduce venlafaxine ER over 1–3 weeks during the tapering period (Supporting Information S1: Figure 1). Prohibited concomitant medication was identical to that of the preceding study and included monoamine oxidase inhibitors, antipsychotics, anxiolytics, hypnotics, and antidepressants. Concomitant treatment of insomnia with nonbenzodiazepine hypnotics (i.e., Z‐drugs) was allowed with restrictions (Supporting Information S2: Table 2).
Participants
Eligible participants were Japanese outpatients aged ≥18 years with a primary diagnosis of GAD who had completed 10 weeks of treatment, including the tapering period during which venlafaxine ER was reduced to 37.5 mg, without any serious protocol deviations and had shown good tolerability to the study intervention in the preceding study. Participants were enrolled immediately after completion of the preceding double‐blind study, and treatment allocation in that study remained blinded until enrollment into this open‐label study was completed. Therefore, participants were enrolled regardless of their remission status or prior treatment assignment, as it was not feasible to selectively exclude patients based on prior placebo exposure. The following participants were considered as ineligible to this study: Those who were determined to be at the risk of suicide, with any serious acute/chronic medical or psychiatric condition, or laboratory abnormality, and who demonstrated any clinically significant abnormalities in physical examination at baseline, or who had not recovered from clinically significant abnormalities in 12‐lead electrocardiogram (ECG) assessment, clinical laboratory tests, or vital signs recorded in the preceding study.
Assessments
Safety and efficacy were assessed at baseline, every week during Weeks 1–4, every 2 weeks during Weeks 6–8, every 4 weeks during Weeks 12–16, and every 6 weeks during Weeks 22–52 in the treatment period. The primary endpoint was the safety endpoint: incidence of adverse events, absolute values, and changes from baseline in body weight, vital signs, clinical laboratory tests, standard ECG, and frequency of suicidal ideation or suicidal behavior using the Columbia‐Suicide Severity Rating Scale. 20 The secondary endpoint was the efficacy endpoint: change from baseline in Hamilton Anxiety Rating Scale (HAM‐A) 21 total score and Clinical Global Impressions 22 ‐Severity of Illness (CGI‐S), and absolute score of CGI‐I. CGI‐I was evaluated based on the baseline status of the preceding study.
Statistical analysis
The sample size was determined based on regulatory requirement of having at least 100 participants completing the 52‐week venlafaxine treatment period, and the result of a long‐term study with venlafaxine for depression in Japan, wherein 76% of the enrolled participants completed the study. 23 Assuming a similar completion rate, the estimated number of participants was set at 132 to ensure at least 100 participants complete the study.
The safety set consisted of all participants who received at least one dose of venlafaxine ER regardless of dosage strength or number of doses. The incidence of adverse events was summarized for all patients as well as for two treatment groups, that is, treatment groups of participants who had received venlafaxine ER (the prior VEN group) or placebo (the prior PBO group) during the preceding study. The efficacy set consisted of all participants who had at least one evaluable assessment of efficacy variables at any time point after baseline. The absolute scores and changes from baseline in HAM‐A total score and CGI‐S as well as the absolute score of CGI‐I were summarized by visit. Outcomes were descriptively summarized according to participants' treatment assignment in the preceding study. These analyses were exploratory, and no statistical comparisons were conducted between the groups, as this long‑term study was not designed to evaluate between‑group differences.
RESULTS
Participants
As per protocol, 135 of the 336 participants of the preceding study consented and were rolled over to this long‐term extension study. Of those, 65 had previously received venlafaxine ER, and 70 had received a placebo. All participants were included in both the safety set and efficacy set. Of the 135 enrolled participants, 113 completed the treatment period (57 in the prior VEN group and 56 in the prior PBO group), and 111 completed the tapering period (57 in the prior VEN group and 54 in the prior PBO group). Of all the enrolled participants, 24 participants (8 in the prior VEN group and 16 in the prior PBO group) discontinued treatment early, mostly due to withdrawal of consent (5 in the prior VEN group and 12 in the prior PBO group) (Figure 1).
Figure 1.
Participant disposition. LTE, long‐term extension.
Overall, the median (range) age was 40 (20‐72) years, and 53.3% of participants were male. Baseline demographic characteristics appeared broadly comparable between both groups. Mean HAM‐A total score at baseline in the prior VEN group was slightly lower than in the prior PBO group (14.9 vs. 16.9). Likewise, baseline mean values of HAM‐A subscores and CGI‐S score in the prior VEN group were somewhat lower than in the prior PBO group (Table 1).
Table 1.
Demographic characteristics (safety set).
| Characteristics | Statistics | Overall (N = 135) | Prior VEN groupa (N = 65) | Prior PBO groupb (N = 70) |
|---|---|---|---|---|
| Sex | ||||
| Male | n (%) | 72 (53.3) | 32 (49.2) | 40 (57.1) |
| Female | n (%) | 63 (46.7) | 33 (50.8) | 30 (42.9) |
| Agec (years) | ||||
| Mean (SD) | 40.4 (12.6) | 39.3 (12.6) | 41.5 (12.6) | |
| Min, median, max | 20, 40.0, 72 | 20, 38.0, 72 | 20, 41.0, 72 | |
| Body weightd (kg) | ||||
| Mean (SD) | 64.26 (13.85) | 64.10 (14.53) | 64.40 (13.29) | |
| Min, median, max | 38.0, 63.90, 106.6 | 41.5, 62.40, 100.6 | 38.0, 66.30, 106.6 | |
| HAM‐A total score | ||||
| Mean (SD) | 15.9 (8.2) | 14.9 (8.6) | 16.9 (7.8) | |
| Min, median, max | 0, 16.0, 43 | 0, 16.0, 43 | 1, 16.5, 42 | |
| HAM‐A psychic anxiety factor | ||||
| Mean (SD) | 8.9 (4.7) | 8.4 (4.8) | 9.4 (4.5) | |
| Min, median, max | 0, 8.0, 24 | 0, 9.0, 23 | 1, 8.0, 24 | |
| HAM‐A somatic anxiety factor | ||||
| Mean (SD) | 7.0 (4.3) | 6.5 (4.3) | 7.5 (4.2) | |
| Min, median, max | 0, 7.0, 20 | 0, 6.0, 20 | 0, 7.0, 18 | |
| CGI‐S | ||||
| Mean (SD) | 3.4 (1.0) | 3.3 (1.1) | 3.5 (0.9) | |
| Min, median, max | 1, 4.0, 6 | 1, 3.0, 6 | 1, 4.0, 6 | |
| Treatment in double‐blind study | ||||
| Venlafaxine | n (%) | 65 (48.1) | 65 (100) | 0 |
| Placebo | n (%) | 70 (51.9) | 0 | 70 (100) |
Note: Percentages (%) are based on the number of participants in the safety set (N).
Abbreviations: CGI‐S, Clinical Global Impressions‐Severity of Illness; HAM‐A, Hamilton Anxiety Rating Scale; max, maximum; min, minimum; n, number of participants within each category; SD, standard deviation.
Treatment group of participants who had received venlafaxine extended release (ER) in the double‐blind study and continued using venlafaxine ER in this study.
Treatment group of participants who had received placebo in the double‐blind study and used venlafaxine ER in this study.
At informed consent.
At baseline.
All of the participants who enrolled into this study achieved treatment adherence of at least 80% (calculated based on days with missed dose or changed dose), and 65.9% of participants achieved 100% treatment adherence (64.6% in the prior VEN group and 67.1% in the prior PBO group). For the doses each participant had received during the treatment period (up to Week 52), 48.9% of participants received 225 mg as the highest dose at some point during the treatment period (41.5% in the prior VEN group and 55.7% in the prior PBO group). The percentages of participants who had received doses at the very end of the treatment period were 0.7% for 37.5 mg, 43.7% for 75 mg, 19.3% for 150 mg, and 36.3% for 225 mg (0% and 1.4% for 37.5 mg, 55.4% and 32.9% for 75 mg, 12.3% and 25.7% for 150 mg, and 32.3% and 40.0% for 225 mg in the prior VEN and the prior PBO groups, respectively) (Table 2).
Table 2.
Summary of maximum dosage, modal dosage, and last dosage by category (safety set).
| Prescribed dose | ||||
|---|---|---|---|---|
| 37.5 mg | 75 mg | 150 mg | 225 mg | |
| n (%) | n (%) | n (%) | n (%) | |
| Overall (N = 135) | ||||
| Maximum dosage | 1 (0.7) | 49 (36.3) | 19 (14.1) | 66 (48.9) |
| Modal dosage | 2 (1.5) | 59 (43.7) | 25 (18.5) | 49 (36.3) |
| Last dosage | 1 (0.7) | 59 (43.7) | 26 (19.3) | 49 (36.3) |
| Prior VEN groupa (N = 65) | ||||
| Maximum dosage | 0 | 32 (49.2) | 6 (9.2) | 27 (41.5) |
| Modal dosage | 0 | 37 (56.9) | 7 (10.8) | 21 (32.3) |
| Last dosage | 0 | 36 (55.4) | 8 (12.3) | 21 (32.3) |
| Prior PBO groupb (N = 70) | ||||
| Maximum dosage | 1 (1.4) | 17 (24.3) | 13 (18.6) | 39 (55.7) |
| Modal dosage | 2 (2.9) | 22 (31.4) | 18 (25.7) | 28 (40.0) |
| Last dosage | 1 (1.4) | 23 (32.9) | 18 (25.7) | 28 (40.0) |
Note: N is the number of participants in the safety set. Percentages (%) are based on the number of participants in the safety set (N). Maximum dosage: maximum dosage in treatment period; modal dosage: modal dosage in treatment period; last dosage: dosage at the end of treatment period. If there are multiple dosages with the same maximum frequency, the highest dosage among them was adopted.
Treatment group of participants who had received venlafaxine extended release (ER) in the double‐blind study and continued using venlafaxine ER in this study.
Treatment group of participants who had received a placebo in the double‐blind study and used venlafaxine ER in this study.
Safety outcome
Overall, 113 participants (83.7%) experienced 392 treatment‐emergent adverse events (TEAEs); 54 participants (83.1%) experienced 152 TEAEs in the prior VEN group, and 59 participants (84.3%) experienced 240 TEAEs in the prior PBO group (Table 3). Among all participants, most frequently reported TEAEs (≥5%) included nasopharyngitis (n = 31, 23.0%), nausea (n = 19, 14.1%), weight increased (n = 18, 13.3%), somnolence (n = 17, 12.6%), constipation (n = 12, 8.9%), dizziness and insomnia (n = 10, 7.4% each), headache (n = 8, 5.9%), and back pain (n = 7, 5.2%). All of the reported TEAEs were mild or moderate in intensity, with the exception of one severe TEAE reported in the prior PBO group. This single severe TEAE was arrhythmia, which was ongoing at the end of the study and was considered as not related to the use of the study intervention.
Table 3.
Overall incidence of adverse events (safety set).
| Adverse event type | Overall (N =135) n (%) [event] | Prior VEN groupa (N =65) n (%) [event] | Prior PBO groupb (N =70) n (%) [event] |
|---|---|---|---|
| TEAEs | 113 (83.7) [392] | 54 (83.1) [152] | 59 (84.3) [240] |
| Drug‐related TEAEs | 69 (51.1) [140] | 33 (50.8) [56] | 36 (51.4) [84] |
| TEAEs by intensity | |||
| Mild | 79 (58.5) [321] | 44 (67.7) [137] | 35 (50.0) [184] |
| Moderate | 33 (24.4) [70] | 10 (15.4) [15] | 23 (32.9) [55] |
| Severe | 1 (0.7) [1] | 0 | 1 (1.4) [1] |
| Serious TEAEs | 0 | 0 | 0 |
| TEAEs leading to study discontinuation | 2 (1.5) [2] | 0 | 2 (2.9) [2] |
| TEAEs leading to death | 0 | 0 | 0 |
| Most common TEAEsc | |||
| Nasopharyngitis | 31 (23.0) [34] | 14 (21.5) [15] | 17 (24.3) [19] |
| Nausea | 19 (14.1) [25] | 7 (10.8) [9] | 12 (17.1) [16] |
| Weight increased | 18 (13.3) [18] | 11 (16.9) [11] | 7 (10.0) [7] |
| Somnolence | 17 (12.6) [18] | 6 (9.2) [6] | 11 (15.7) [12] |
| Constipation | 12 (8.9) [14] | 4 (6.2) [5] | 8 (11.4) [9] |
| Dizziness | 10 (7.4) [11] | 5 (7.7) [5] | 5 (7.1) [6] |
| Insomnia | 10 (7.4) [11] | 4 (6.2) [4] | 6 (8.6) [7] |
| Headache | 8 (5.9) [9] | 1 (1.5) [1] | 7 (10.0) [8] |
| Back pain | 7 (5.2) [7] | 2 (3.1) [2] | 5 (7.1) [5] |
Note: Percentages (%) are based on the number of participants in the safety set in each treatment group (N). The number of participants with at least 1 event is summarized for each type of event.
Abbreviations: n, number of participants within each category/event; TEAE, treatment‐emergent adverse event.
Treatment group of participants who had received venlafaxine extended release (ER) in the double‐blind study and continued using venlafaxine ER in this study.
Treatment group of participants who had received a placebo in the double‐blind study and used venlafaxine ER in this study.
Overall incidence ≥ 5%.
No serious TEAE or death was reported during the study. Two TEAEs (nervousness and depression) leading to study discontinuation were reported in two participants of the prior PBO group, one of which was considered related to the use of venlafaxine ER, that is, nervousness. Overall, six participants (4.4%) experienced six events of withdrawal syndrome (three participants in each group), most of which occurred around Week 53. Most of the events were mild in intensity and resolved without any modification of the study intervention. Of the six events, five were assessed as related to the study intervention.
Adverse events known to occur when venlafaxine ER is administered at high doses included tachycardia, high blood pressure, QTc prolongation, and hepatic impairment. 24 , 25 In the present study, events related to tachycardia (sinus tachycardia, arrhythmia, sinus bradycardia, and tachycardia) were reported in less than three participants (<2.2%). Events of hypertension and increased blood pressure were reported in four participants (3.0%) (four in the prior VEN group) and three participants (2.2%) (one in the prior VEN group and two in the prior PBO group), respectively. Regarding events of hepatic impairment, increased alanine aminotransferase (ALT), hepatic function abnormal, increased aspartate aminotransferase (AST), and increased values of multiple liver function tests (ALT and total bilirubin) were reported in four participants (3.0%) (two in the prior VEN group and two in the prior PBO group), three participants (2.2%) (three in the prior PBO group), two participants (1.5%) (two in the prior PBO group), and one participant (0.7%) (the prior VEN group), respectively. No event of QTc prolongation was reported as a TEAE. None of these events led to treatment or study discontinuation.
Overall, no clinically significant abnormality in the QTcF value (≥500 ms) was reported. A QTcF in the range of 480 to ≤500 ms was observed in one participant in the prior VEN group, and QTcF increases of 30 to <60 ms from baseline were reported in one participant in the prior VEN group and two participants in the prior PBO group, but none of them was considered as clinically significant. ECG interpretation was normal in most of the participants during the study. There were no clinically significant changes in hematology, chemistry, urinalysis, or physical examination parameters during the study.
Across the treatment, tapering, and follow‐up periods, suicidal ideation was reported in 11 participants (8.1%) (5 [7.7%] in the prior VEN group and 6 [8.6%] in the prior PBO group); C‐SSRS category “1. Wish to be dead” in 8.1%, and “2. Non‐specific active suicidal thoughts” in 3.0%. Suicidal behavior was not reported in either group.
Efficacy outcome
A consistent decrease in mean HAM‐A total score over time was observed during the study (Figure 2). The overall mean (SD) change from baseline in HAM‐A total score at Week 52 was −8.3 (7.5): −7.8 (6.7) in the prior VEN group and −8.7 (8.3) in the prior PBO group (Table 4).
Figure 2.
Observed Hamilton Anxiety Rating Scale (HAM‐A) total scores by visit during the study (efficacy set). Prior VEN = treatment group of participants who had received venlafaxine extended release (ER) in the double‐blind study and continued using venlafaxine ER in this study. Prior PBO = treatment group of participants who had received placebo in the double‐blind study and used venlafaxine ER in this study.
Table 4.
Change from baseline to Week 52 in Hamilton Anxiety Rating Scale (HAM‐A) total scores (efficacy set).
| Group observed/change statistics | Baseline | Week 12 | Week 28 | Week 52 |
|---|---|---|---|---|
| Overall (N = 135) | ||||
| Observed | ||||
| n | 135 | 126 | 118 | 111 |
| Mean (SD) | 15.9 (8.2) | 10.1 (6.9) | 8.6 (6.7) | 8.0 (7.1) |
| Min, median, max | 0, 16.0, 43 | 0, 8.5, 40 | 0, 7.0, 37 | 0, 6.0, 40 |
| Change | ||||
| n | ‐ | 126 | 118 | 111 |
| Mean (SD) | ‐ | −6.0 (6.8) | −7.3 (7.1) | −8.3 (7.5) |
| Min, median, max | ‐ | −28, −5.0, 12 | −29, −6.0, 11 | −30, −6.0, 5 |
| Prior VEN groupa (N = 65) | ||||
| Observed | ||||
| n | 65 | 63 | 60 | 57 |
| Mean (SD) | 14.9 (8.6) | 9.5 (7.2) | 8.1 (7.0) | 7.5 (6.9) |
| Min, median, max | 0, 16.0, 43 | 0, 8.0, 40 | 0, 7.0, 37 | 0, 6.0, 40 |
| Change | ||||
| n | ‐ | 63 | 60 | 57 |
| Mean (SD) | ‐ | −5.6 (5.8) | −6.9 (5.9) | −7.8 (6.7) |
| Min, median, max | ‐ | −22, −4.0, 3 | −24, −6.0, 3 | −26, −7.0, 4 |
| Prior PBO groupb (N = 70) | ||||
| Observed | ||||
| n | 70 | 63 | 58 | 54 |
| Mean (SD) | 16.9 (7.8) | 10.6 (6.5) | 9.0 (6.4) | 8.5 (7.4) |
| Min, median, max | 1, 16.5, 42 | 0, 9.0, 26 | 0, 8.0, 28 | 0, 6.5, 37 |
| Change | ||||
| n | ‐ | 63 | 58 | 54 |
| Mean (SD) | ‐ | −6.4 (7.7) | −7.7 (8.1) | −8.7 (8.3) |
| Min, median, max | ‐ | −28, −5.0, 12 | −29, −6.5, 11 | −30, −6.0, 5 |
Note: N is the number of participants in the efficacy set.
Abbreviations: max, maximum; min, minimum; n, number of participants with non‐missing value; SD, standard deviation.
Treatment group of participants who had received venlafaxine extended release (ER) in the double‐blind study and continued using venlafaxine ER in this study.
Treatment group of participants who had received placebo in the double‐blind study and used venlafaxine ER in this study.
The overall mean (SD) change from baseline in HAM‐A psychic anxiety factor at Week 52 was −4.8 (4.6): −4.6 (4.1) in the prior VEN group and −5.1 (5.1) in the prior PBO group. Mean scores at Week 52 were almost half of baseline scores in both groups (4.1 from 8.4 in the prior VEN group and 4.7 from 9.4 in the prior PBO group), indicating a favorable change in HAM‐A psychic anxiety factor at Week 52. The overall mean (SD) change from baseline in HAM‐A somatic anxiety factor at Week 52 was −3.4 (3.5): −3.2 (3.3) in the prior VEN group and −3.7 (3.8) in the prior PBO group. Similar to HAM‐A psychic anxiety factor, mean scores at Week 52 were almost half of baseline scores in both groups (3.4 from 6.5 in the prior VEN group and 3.8 from 7.5 in the prior PBO group), also indicating an evident change in HAM‐A somatic anxiety factor at Week 52 (Table 5).
Table 5.
Change from baseline to Week 52 in Hamilton Anxiety Rating Scale (HAM‐A) psychic/somatic anxiety factor and Clinical Global Impressions‐Severity of Illness (CGI‐S)/Clinical Global Impressions‐Global Improvement (CGI‐I) (efficacy set).
| Group observed/change statistics | Baseline | Week 12 | Week 28 | Week 52 |
|---|---|---|---|---|
| HAM‐A psychic anxiety factor | ||||
| Overall (N = 135) | ||||
| Observed | ||||
| n | 135 | 126 | 118 | 111 |
| Mean (SD) | 8.9 (4.7) | 5.5 (3.9) | 4.7 (3.8) | 4.4 (4.1) |
| Min, median, max | 0, 8.0, 24 | 0, 5.0, 22 | 0, 4.0, 18 | 0, 4.0, 20 |
| Change | ||||
| n | ‐ | 126 | 118 | 111 |
| Mean (SD) | ‐ | −3.4 (4.1) | −4.2 (4.3) | −4.8 (4.6) |
| Min, median, max | ‐ | −16, −3.0, 6 | −16, −3.0, 11 | −16, −4.0, 6 |
| Prior VEN groupa (N = 65) | ||||
| Observed | ||||
| n | 65 | 63 | 60 | 57 |
| Mean (SD) | 8.4 (4.8) | 5.0 (3.8) | 4.4 (3.7) | 4.1 (3.8) |
| Min, median, max | 0, 9.0, 23 | 0, 4.0, 22 | 0, 4.0, 17 | 0, 4.0, 20 |
| Change | ||||
| n | ‐ | 63 | 60 | 57 |
| Mean (SD) | ‐ | −3.5 (3.5) | −4.1 (3.6) | −4.6 (4.1) |
| Min, median, max | ‐ | −16, −2.0, 3 | −14, −3.0, 2 | −16, −3.0, 6 |
| Prior PBO groupb (N = 70) | ||||
| Observed | ||||
| n | 70 | 63 | 58 | 54 |
| Mean (SD) | 9.4 (4.5) | 6.1 (4.0) | 4.9 (3.9) | 4.7 (4.4) |
| Min, median, max | 1, 8.0, 24 | 0, 5.0, 19 | 0, 5.0, 18 | 0, 4.0, 20 |
| Change | ||||
| n | ‐ | 63 | 58 | 54 |
| Mean (SD) | ‐ | −3.3 (4.6) | −4.4 (5.0) | −5.1 (5.1) |
| Min, median, max | ‐ | −14, −3.0, 6 | −16, −3.5, 11 | −16, −4.5, 5 |
| HAM‐A somatic anxiety factor | ||||
| Overall (N = 135) | ||||
| Observed | ||||
| n | 135 | 126 | 118 | 111 |
| Mean (SD) | 7.0 (4.3) | 4.5 (3.6) | 3.9 (3.5) | 3.6 (3.5) |
| Min, median, max | 0, 7.0, 20 | 0, 4.0, 18 | 0, 3.0, 20 | 0, 2.0, 20 |
| Change | ||||
| n | ‐ | 126 | 118 | 111 |
| Mean (SD) | ‐ | −2.6 (3.3) | −3.1 (3.4) | −3.4 (3.5) |
| Min, median, max | ‐ | −14, −2.0, 6 | −14, −2.0, 5 | −14, −2.0, 2 |
| Prior VEN groupa (N = 65) | ||||
| Observed | ||||
| n | 65 | 63 | 60 | 57 |
| Mean (SD) | 6.5 (4.3) | 4.5 (3.8) | 3.7 (3.7) | 3.4 (3.5) |
| Min, median, max | 0, 6.0, 20 | 0, 4.0, 18 | 0, 3.0, 20 | 0, 2.0, 20 |
| Change | ||||
| n | ‐ | 63 | 60 | 57 |
| Mean (SD) | ‐ | −2.1 (2.9) | −2.8 (2.9) | −3.2 (3.3) |
| Min, median, max | ‐ | −9, −2.0, 5 | −10, −2.0, 2 | −12, −2.0, 1 |
| Prior PBO groupb (N = 70) | ||||
| Observed | ||||
| n | 70 | 63 | 58 | 54 |
| Mean (SD) | 7.5 (4.2) | 4.5 (3.3) | 4.1 (3.3) | 3.8 (3.5) |
| Min, median, max | 0, 7.0, 18 | 0, 4.0, 12 | 0, 3.0, 13 | 0, 2.5, 17 |
| Change | ||||
| n | ‐ | 63 | 58 | 54 |
| Mean (SD) | ‐ | −3.1 (3.7) | −3.4 (3.8) | −3.7 (3.8) |
| Min, median, max | ‐ | −14, −3.0, 6 | −14, −2.5, 5 | −14, −3.0, 2 |
| CGI‐S | ||||
| Overall (N = 135) | ||||
| Observed | ||||
| n | 135 | 126 | 118 | 111 |
| Mean (SD) | 3.4 (1.0) | 2.7 (1.0) | 2.5 (1.0) | 2.4 (1.0) |
| Min, median, max | 1, 4.0, 6 | 1, 3.0, 5 | 1, 3.0, 5 | 1, 2.0, 5 |
| Change | ||||
| n | ‐ | 126 | 118 | 111 |
| Mean (SD) | ‐ | −0.7 (1.0) | −1.0 (1.1) | −1.1 (1.2) |
| Min, median, max | ‐ | −4, 0.0, 2 | −5, −1.0, 2 | −5, −1.0, 1 |
| Prior VEN groupa (N = 65) | ||||
| Observed | ||||
| n | 65 | 63 | 60 | 57 |
| Mean (SD) | 3.3 (1.1) | 2.6 (1.0) | 2.4 (1.0) | 2.3 (1.0) |
| Min, median, max | 1, 3.0, 6 | 1, 3.0, 5 | 1, 2.0, 5 | 1, 2.0, 5 |
| Change | ||||
| n | ‐ | 63 | 60 | 57 |
| Mean (SD) | ‐ | −0.7 (0.9) | −0.9 (1.0) | −1.1 (1.0) |
| Min, median, max | ‐ | −3, 0.0, 1 | −3, −1.0, 1 | −3, −1.0, 1 |
| Prior PBO groupb (N = 70) | ||||
| Observed | ||||
| n | 70 | 63 | 58 | 54 |
| Mean (SD) | 3.5 (0.9) | 2.8 (1.0) | 2.5 (1.0) | 2.4 (1.1) |
| Min, median, max | 1, 4.0, 6 | 1, 3.0, 5 | 1, 3.0, 5 | 1, 3.0, 4 |
| Change | ||||
| n | ‐ | 63 | 58 | 54 |
| Mean (SD) | ‐ | −0.7 (1.2) | −1.0 (1.3) | −1.2 (1.3) |
| Min, median, max | ‐ | −4, 0.0, 2 | −5, −1.0, 2 | −5, −1.0, 1 |
| CGI‐I c | ||||
| Overall (N = 135) | ||||
| Observed | ||||
| n | 135 | 126 | 118 | 111 |
| Mean (SD) | 2.7 (1.1) | 2.1 (0.9) | 1.8 (0.9) | 1.7 (0.9) |
| Min, median, max | 1, 3.0, 5 | 1, 2.0, 5 | 1, 2.0, 5 | 1, 1.0, 5 |
| Prior VEN groupa (N = 65) | ||||
| Observed | ||||
| n | 65 | 63 | 60 | 57 |
| Mean (SD) | 2.6 (1.2) | 1.9 (0.9) | 1.7 (0.9) | 1.6 (0.9) |
| Min, median, max | 1, 3.0, 5 | 1, 2.0, 4 | 1, 1.0, 4 | 1, 1.0, 5 |
| Prior PBO groupb (N = 70) | ||||
| Observed | ||||
| n | 70 | 63 | 58 | 54 |
| Mean (SD) | 2.9 (1.0) | 2.2 (1.0) | 1.9 (1.0) | 1.8 (1.0) |
| Min, median, max | 1, 3.0, 5 | 1, 2.0, 5 | 1, 2.0, 5 | 1, 2.0, 5 |
Note: N is the number of participants in the efficacy set.
Abbreviations: max, maximum; min, minimum; n, number of participants with non‐missing value; SD, standard deviation.
Treatment group of participants who had received venlafaxine extended release (ER) in the double‐blind study and continued using venlafaxine ER in this study.
Treatment group of participants who had received placebo in the double‐blind study and used venlafaxine ER in this study.
CGI‐I was evaluated based on the baseline status of the preceding study.
The overall mean (SD) change from baseline in CGI‐S at Week 52 was −1.1 (1.2): −1.1 (1.0) in the prior VEN group and −1.2 (1.3) in the prior PBO group. The overall mean (SD) CGI‐I score decreased from baseline (2.7 [1.1]) to Week 52 (1.7 [0.9]): 2.6 (1.2) to 1.6 (0.9) in the prior VEN group and 2.9 (1.0) to 1.8 (1.0) in the prior PBO group. Favorable findings were observed at Week 52 in both CGI‐S and CGI‐I scores.
Remission in HAM‐A total score was defined as a score of ≤7. Overall remission rate in HAM‐A total score increased from baseline (17.0%) to Week 52 (57.7%): 24.6%–59.6% in the prior VEN group and 10.0%–55.6% in the prior PBO group, continuously demonstrating improved treatment responses in both groups (Figure 3).
Figure 3.
Remission rate by visit (efficacy set). Prior VEN = treatment group of participants who had received venlafaxine extended release (ER) in the double‐blind study and continued using venlafaxine ER in this study. Prior PBO = treatment group of participants who had received placebo in the double‐blind study and used venlafaxine ER in this study. Remission: HAM‐A total score of 7 or less. CI, confidence interval; n, number of participants with non‐missing value. N is the number of participants in the full analysis set in each treatment group. †Clopper‐Pearson confidence interval.
DISCUSSION
The present study is the first to report the long‐term safety of venlafaxine ER in Japanese patients with GAD. Venlafaxine ER has been used for a prolonged period in treating depression, whereas its approval for GAD in Japan is relatively recent. Venlafaxine has been approved and used for GAD in several countries, and its safety and efficacy in the indication GAD have been established outside Japan. We report the results of safety and efficacy for long‐term use (52 weeks) of venlafaxine ER 75–225 mg/day in 135 Japanese participants who were rolled over from a previous 10‐week, double‐blind, randomized, Phase 3 study. 19 The dosage and administration of venlafaxine ER for the present study were the same as those for the approved indication of depression or a depressive state in Japan and the approved indications of MDD and GAD outside Japan. This long‐term extension study was conducted to evaluate the safety and efficacy of venlafaxine in Japanese patients with GAD, with results that may support treatment decisions in patients diagnosed with the condition in the future. In this study, results were summarized by participants' prior treatment assignment in the preceding study to provide descriptive context regarding their clinical course. An additional exploratory analysis compared early‑period safety outcomes between participants who had received venlafaxine or placebo during the preceding study. During the first three months, the incidence of TEAEs tended to be slightly higher in the prior PBO group than in the prior VEN group (Supporting Information S2: Table 3). However, because no statistical comparisons were conducted between the groups, these findings should be interpreted as exploratory, and no conclusions regarding differences between the groups can be drawn.
Because all participants receiving venlafaxine ER in the preceding study underwent a 2‑week tapering period and had their dose reduced to 37.5 mg before entering this study, no dose discontinuity occurred at the transition. Therefore, the influence of dosing at entry on early adverse events or symptom trajectories was considered minimal.
Gender, age, and body weight were balanced between the two groups related to the previous study intervention in the preceding study (the prior VEN group and the prior PBO group). Baseline mean scores of HAM‐A (total and subscores) and CGI‐S were slightly lower in the prior VEN group than in the prior PBO group. From Week 3 to Week 52, more than half of the participants in the prior VEN group consistently received 75 mg, suggesting that lower doses were maintained throughout long‑term treatment. However, because eligibility for this study required good tolerability in the preceding study, tolerability‑driven dose reductions or adverse events are unlikely to explain the continued use of lower doses. Some participants in the prior VEN group may also have entered the study already in remission, reducing the need for higher doses. Therefore, conclusions regarding the feasibility of long‑term management with lower doses should be interpreted cautiously.
Venlafaxine ER 75–225 mg/day was well tolerated over the long‐term use of 52 weeks with an acceptable safety profile in Japanese adult patients with GAD. The overall safety profile was consistent with that observed in the preceding study 19 and in the approved indication of depression or a depressive state in Japan. No relevant deviations from the drug profile already established for other ethnic groups have been observed, nor have new safety concerns been detected. The most common TEAEs reported in the venlafaxine group of the preceding study, including somnolence, nausea, constipation, nasopharyngitis, insomnia, and headache, 19 were also reported in this study, most of which were mild in intensity. While there were TEAEs leading to dose changes, a low incidence of TEAEs leading to study discontinuation was only observed in the prior PBO group. Neither death nor SAEs were reported during this study. These findings suggest that the observed TEAEs can be managed even during long‐term treatment. Events suspected to occur with use of venlafaxine at higher doses and over longer treatment periods, such as QTc prolongation and hepatic impairment, 24 , 25 were absent or limited in this study, and none of them led to treatment discontinuation. In addition, no concerns of increased risks were identified regarding changes in ECG parameters or suicidal ideation with long‐term use and with higher doses of treatment. A risk assessment for potential risks including suicide/suicidal thoughts was performed. Careful monitoring of suicidal ideation did not reveal new patterns for onset of suicidal ideation; no adverse events related to suicide were reported, and numerically, an even lower incidence of suicidal ideation was reported in the prior VEN group than in the prior PBO group. No clinically significant changes in laboratory tests and physical examinations were observed during the study. Overall, no new safety concerns were identified; however, careful monitoring of patients and follow‐up of identified risks should be practiced.
The overall results of the mean HAM‐A total score showed a consistent decrease over time. Notably, the scores showed a tendency to further decrease during long‐term treatment in the participants who had received venlafaxine ER in the preceding study (the prior VEN group). Although a few participants in both groups showed a certain degree of high scores at selected individual time points, the mean baseline score was lower in the prior VEN group than that in the prior PBO group, and the mean scores in both groups decreased generally in the same manner toward Week 52. For the categories of psychic and somatic anxiety factors, the mean scores for each factor at Week 52 reached almost half of the baseline scores in both groups. Correspondingly, the overall remission rate in HAM‐A total score (scores of ≤7) increased from baseline to Week 52, which may indicate sustained symptom improvement during continued treatment with venlafaxine ER. Because eligibility for the study did not require a minimum HAM‑A score, some participants, including approximately 10% in the prior PBO group, entered the study in remission. Their inclusion reflects the primary focus on long‑term safety rather than efficacy selection criteria and is consistent with clinical practice, where pharmacotherapy may be maintained or initiated to support sustained remission and reduce relapse risk. The change from baseline in CGI‐S and the mean score of CGI‐I at Week 52 were also consistent with ongoing symptomatic improvement over the long‑term treatment period. These efficacy results detected no further issues compared with the preceding study. 19
According to major international clinical guidelines, 10 , 26 , 27 pharmacological treatment for anxiety disorders including GAD is recommended to be maintained for 6–12 months following remission, in order to reduce the risk of relapse. In this study, the safety of venlafaxine ER over the recommended period of 6–12 months was confirmed, and no safety concerns were observed.
This study has several limitations. First, as an open‑label study, the generalizability of the findings is limited. Participants represented a selected population who had completed the prior 10‑week study without major protocol deviations and showed good tolerability to venlafaxine ER (if applicable). Consequently, the incidence of antidepressant‑associated adverse events may be lower than in broader clinical populations, 28 and the study sample may not fully reflect routine clinical practice. Second, because this study did not include a placebo‑controlled comparator, the ability to evaluate the relapse‑preventive efficacy of venlafaxine ER is limited; the findings should therefore be interpreted primarily in the context of long‑term safety and maintenance of therapeutic effects. Third, post‑randomization selection led to inherent differences between the prior‑treatment groups: patients in the prior venlafaxine ER group had already been exposed to the drug, whereas those in the prior placebo group were newly exposed during this study. As a result, early‑phase effects such as the incidence of TEAEs, discontinuations, and AE‐related dose adjustments may differ between the prior‑treatment groups, and pooled or overall summaries should be interpreted with caution. Finally, social background information and detailed clinical history were not collected, which further limits the assessment of generalizability and potential factors related to discontinuation.
In conclusion, this 52‐week long‐term, open‐label, extension study demonstrated that long‐term use of venlafaxine ER 75–225 mg/day is generally safe, well‐tolerated, and associated with sustained therapeutic effects in Japanese adult patients with GAD who continued treatment. Consistency of the descriptive findings supports the overall long‐term safety and effectiveness of venlafaxine ER for the indication of GAD in the Japanese patient population, aligning with the findings of the preceding short‐term double‐blind study. 19
AUTHOR CONTRIBUTIONS
Tempei Otsubo, Koichiro Watanabe, Takeshi Inoue, Ataru Inagaki, Toshiaki Kikuchi, Keisuke Nomoto, Shingo Higa, Yuko Asami, Bin Sun, and Kristina Marschall contributed to the conception and design of the study. Bin Sun contributed to the acquisition and analysis of data. All authors contributed to the interpretation of results and to the drafting and review of this manuscript.
CONFLICT OF INTEREST STATEMENT
Tempei Otsubo served as a medical consultant in this study, and received consulting fee and speaker fee, as well as personal compensation from Viatris Pharmaceuticals Japan, Takeda Pharmaceutical, Otsuka Pharmaceutical, and Sumitomo Pharma. Koichiro Watanabe served as a medical consultant in this study, and received grants from Eisai, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Otsuka Pharmaceutical, Sumitomo Pharma, and Takeda Pharmaceutical; speaker's honoraria from Astra Zeneca, Boehringer Ingelheim, Eisai, Janssen Pharmaceutical, Kyowa Pharmaceutical, Lundbeck Japan, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Otsuka Pharmaceutical, Shionogi, Sumitomo Pharma, Takeda Pharmaceutical, Teijin Pharma, and Viatris; and consulting fees from Boehringer Ingelheim, Daiichi Sankyo, Eisai, Janssen Pharmaceutical, Kyowa Pharmaceutical, Lundbeck Japan, Luye Pharma, Mitsubishi Tanabe Pharma, Nippon Chemiphar, Otsuka Pharmaceutical, Sumitomo Pharma, Takeda Pharmaceutical, and Viatris. Takeshi Inoue has received personal compensation from Mochida Pharmaceutical, Takeda Pharmaceutical, Eli Lilly, Janssen Pharmaceutical, MSD, Yoshitomiyakuhin, Mitsubishi Tanabe Pharma, Meiji Seika Pharma, Lundbeck, Nippon Boehringer Ingelheim, and Viatris Pharmaceuticals Japan; grants and personal compensation from Shionogi, Eisai, Otsuka Pharmaceutical, Sumitomo Pharma, Daiichi Sankyo, and Kyowa Pharmaceutical Industry; and is a member of the advisory boards of Viatris Pharmaceuticals Japan, Takeda Pharmaceutical, Nippon Boehringer Ingelheim, and Otsuka Pharmaceutical. Ataru Inagaki served as a medical consultant in this study; has received honoraria or consulting fee from Mitsubishi Tanabe Pharma, IQVIA Services Japan, Meiji Seika Pharma, Janssen Pharmaceutical, and Creativ‐Ceutical; and took part of a research group which is funded by Otsuka Pharmaceutical, Shionogi, Sumitomo Pharma, Takeda Pharmaceutical, Meiji Seika Pharma, and Janssen Pharmaceutical. Toshiaki Kikuchi served as a medical consultant in this study, and has received speaker's honoraria or consultation fee from Mochida Pharmaceutical, Sumitomo Pharma, Takeda Pharmaceutical, Lundbeck Japan, Otsuka Pharmaceutical, and Viatris Pharmaceuticals Japan. Keisuke Nomoto, Shingo Higa, Yuko Asami, Bin Sun, and Kristina Marschall are employees of Viatris.
ETHICS APPROVAL STATEMENT
The study was conducted across 30 study sites in Japan and approved by the institutional review boards (Supporting Information S2: Table 1).
PATIENT CONSENT STATEMENT
Written informed consent was obtained from all subjects prior to study participation and before any protocol‐specified procedures, in accordance with the Declaration of Helsinki and ICH GCP.
CLINICAL TRIAL REGISTRATION
The study was registered in the Japan Registry of Clinical Trials in January 2023 (jRCT2031220234).
Supporting information
Supplemental Figure 1 Study design.
Supplemental Table 1 List of institutional review boards (IRBs).
Supplemental Table 2 Prohibited concomitant medications/therapies and concomitant medications allowed with restrictions.
Supplemental Table 3 Treatment‐emergent adverse events by period.
ACKNOWLEDGMENTS
This study was funded, and study drugs were supplied by Viatris. The authors are grateful to trial participants, investigators at the study sites, and all the personnel who contributed to complete this clinical study. The authors would like to express their sincere gratitude to the late Dr. Yoshinori Watanabe at the Himorogi Psychiatric Institute for his invaluable assistance in carrying out this study. The authors are also grateful to the journal reviewers for insightful comments and suggestions that helped improve the content and presentation of this article. Medical writing services were provided by IQVIA services Japan and funded by Viatris.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
REFERENCES
- 1. American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders Fifth Edition, Text Revision (DSM‐5‐TR™). Washington (DC): American Psychiatric Association; 2022. [Google Scholar]
- 2. DeGeorge KC, Grover M, Streeter GS. Generalized anxiety disorder and panic disorder in adults. Am Fam Physician. 2022;106(2):157–164. [PubMed] [Google Scholar]
- 3. American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders (DSM‐5™). 5th ed. Washington (DC): American Psychiatric Association; 2013. [Google Scholar]
- 4. Crocq MA. The history of generalized anxiety disorder as a diagnostic category. Dialogues Clin Neurosci. 2017;19(2):107–116. 10.31887/DCNS.2017.19.2/macrocq [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Fagan HA, Baldwin DS. Pharmacological treatment of generalised anxiety disorder: current practice and future directions. Expert Rev Neurother. 2023;23(6):535–548. 10.1080/14737175.2023.2211767 [DOI] [PubMed] [Google Scholar]
- 6. Stein DJ, Kazdin AE, Ruscio AM, Chiu WT, Sampson NA, Ziobrowski HN, et al. Perceived helpfulness of treatment for generalized anxiety disorder: a World Mental Health Surveys report. BMC Psychiatry. 2021;21(1):392. 10.1186/s12888-021-03363-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Matsuyama S, Otsubo T, Nomoto K, Higa S, Takashio O. Prevalence of generalized anxiety disorder in Japan: a general population survey. Neuropsychiatr Dis Treat. 2024;20:1355–1366. 10.2147/NDT.S456272 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Katzman MA. Current considerations in the treatment of generalized anxiety disorder. CNS Drugs. 2009;23(2):103–120. 10.2165/00023210-200923020-00002 [DOI] [PubMed] [Google Scholar]
- 9.National Institute for Health and Care Excellence. Generalised anxiety disorder and panic disorder in adults [updated 2020 Jun 15; cited 2025 Jun 10]. Available from: https://www.nice.org.uk/guidance/cg113 [PubMed]
- 10. Katzman MA, Bleau P, Blier P, Chokka P, Kjernisted K, Ameringen MV, et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive‐compulsive disorders. BMC Psychiatry. 2014;14(Suppl 1):S1. 10.1186/1471-244X-14-S1-S1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Bandelow B, Michaelis S, Wedekind D. Treatment of anxiety disorders. Dialogues Clin Neurosci. 2017;19(2):93–107. 10.31887/DCNS.2017.19.2/bbandelow [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Nomoto K, Takashio O, Matsuyama S, Higa S, Otsubo T. Diagnosis and treatment of generalized anxiety disorder in Japan: psychiatric specialist survey. Neuropsychiatr Dis Treat. 2024;20:1001–1010. 10.2147/NDT.S456276 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Effexor® (venlafaxine) SR capsules package insert. Viatris Pharmaceuticals Japan G.K.; 2015 [revised 2026 Mar] (in Japanese) [cited 2026 Mar 24]. Available from: https://pins.japic.or.jp/pdf/newPINS/00065954.pdf
- 14. Rickels K, Pollack MH, Sheehan DV, Haskins JT. Efficacy of extended‐release venlafaxine in nondepressed outpatients with generalized anxiety disorder. Am J Psychiatry. 2000;157(6):968–974. 10.1176/appi.ajp.157.6.968 [DOI] [PubMed] [Google Scholar]
- 15. Davidson JRT, DuPont RL, Hedges D, Haskins JT. Efficacy, safety, and tolerability of venlafaxine extended release and buspirone in outpatients with generalized anxiety disorder. J Clin Psychiatry. 1999;60(8):528–535. 10.4088/jcp.v60n0805 [DOI] [PubMed] [Google Scholar]
- 16. Hackett D, Haudiquet V, Salinas E. A method for controlling for a high placebo response rate in a comparison of venlafaxine XR and diazepam in the short‐term treatment of patients with generalised anxiety disorder. Eur Psychiatry. 2003;18(4):182–187. 10.1016/S0924-9338(03)00046-4 [DOI] [PubMed] [Google Scholar]
- 17. Allgulander C, Hackett D, Salinas E. Venlafaxine extended release (ER) in the treatment of generalised anxiety disorder: twenty‐four‐week placebo‐controlled dose‐ranging study. Br J Psychiatry. 2001;179:15–22. 10.1192/bjp.179.1.15 [DOI] [PubMed] [Google Scholar]
- 18. Gelenberg AJ, Lydiard RB, Rudolph RL, Aguiar L, Haskins JT, Salinas E. Efficacy of venlafaxine extended‐release capsules in nondepressed outpatients with generalized anxiety disorder: a 6‐month randomized controlled trial. JAMA. 2000;283(23):3082–3088. 10.1001/jama.283.23.3082 [DOI] [PubMed] [Google Scholar]
- 19. Otsubo T, Watanabe K, Inoue T, Inagaki A, Kikuchi T, Nomoto K, et al. A randomized, double‐blinded, placebo‐controlled study to evaluate the efficacy and safety of venlafaxine extended release in Japanese patients with generalized anxiety disorder. Psychiatry Clin Neurosci. 2025;79(12):849–858. 10.1111/pcn.13907 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia‐Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266–1277. 10.1176/appi.ajp.2011.10111704 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32(1):50–55. 10.1111/j.2044-8341.1959.tb00467.x [DOI] [PubMed] [Google Scholar]
- 22. Guy W. ECDEU assessment manual for psychopharmacology, revised. National Institute of Mental Health; 1976. p. 218–222 [Google Scholar]
- 23. Higuchi T, Kamijima K, Nakagome K, Itamura R, Asami Y, Kuribayashi K, et al. A randomized, double‐blinded, placebo‐controlled study to evaluate the efficacy and safety of venlafaxine extended release and a long‐term extension study for patients with major depressive disorder in Japan. Int Clin Psychopharmacol. 2016;31(1):8–19. 10.1097/YIC.0000000000000105 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Howell C, Wilson AD, Waring WS. Cardiovascular toxicity due to venlafaxine poisoning in adults: a review of 235 consecutive cases. Br J Clin Pharmacol. 2007;64(2):192–197. 10.1111/j.1365-2125.2007.02849.x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Fang L, Wang S, Cao L, Yao K. Early intervention of acute liver injury related to venlafaxine: a case report. Medicine (Baltimore). 2021;100(49):e28140. 10.1097/MD.0000000000028140 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Bandelow B, Allgulander C, Baldwin DS, da Conceição Costa DL, Denys D, Dilbaz N, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for treatment of anxiety, obsessive–compulsive and posttraumatic stress disorders—Version 3. Part I: anxiety disorders. World J Biol Psychiatry. 2023;24(2):79–117. 10.1080/15622975.2022.2086295 [DOI] [PubMed] [Google Scholar]
- 27. Bandelow B, Werner AM, Kopp I, Rudolf S, Wiltink J, Beutel ME. The German guidelines for the treatment of anxiety disorders: first revision. Eur Arch Psychiatry Clin Neurosci. 2022;272(4):571–582. 10.1007/s00406-021-01324-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Kelly K, Posternak M, Alpert JE. Toward achieving optimal response: understanding and managing antidepressant side effects. Dialogues Clin Neurosci. 2008;10(4):409–418. 10.31887/DCNS.2008.10.4/kkelly [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental Figure 1 Study design.
Supplemental Table 1 List of institutional review boards (IRBs).
Supplemental Table 2 Prohibited concomitant medications/therapies and concomitant medications allowed with restrictions.
Supplemental Table 3 Treatment‐emergent adverse events by period.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.